OVERVIEW: What every clinician needs to know
Pathogen name and classification
What is the best treatment?
For treatment of otitis media in children, amoxicillin, 30mg/kg, three times daily, is recommended, based on the following reasoning:
S. pneumoniae is the most common identifiable cause of otitis and the one associated with the greatest morbidity.
Penicillin-susceptible and intermediately resistant pneumococci are likely to respond better to this treatment than to any other.
No other oral therapy is likely to be more effective for resistant pneumococci.Related Content
Because of the high rate of spontaneous resolution, the American Academy of Pediatrics has subsequently recommended watchful waiting for children aged greater than 2 years unless severe pain or high fever are present, and these recommendations seem appropriate for adults, as well. When adults are treated, amoxicillin should be given at 500mg four times daily. If this treatment fails, amoxicillin/clavulanic acid, a fluoroquinolone or ceftriaxone can be used. In the absence of a perforated tympanic membrane or some other complication, therapy need not be continued beyond 5 days.
Because of similarities in pathogenesis and causative organisms, the same considerations apply to the treatment of acute sinusitis. Amoxicillin is first-line therapy, with a likely beneficial effect in 80 to 90% of cases; amoxicillin/clavulanic acid, with a slightly higher likelihood of success because of efficacy against beta-lactamase producing Haemophilus influenzae, is the backup in cases of failure. Treatment should be given for 5 days; numerous studies and meta-analyses have shown no benefit from more prolonged therapy. Unlike children, for whom quinolones have not been approved, adults can be treated with this class of drugs. Ceftriaxone is the fall-back choice, and failure after this antibiotic has been tried is likely to require referral to an otolaryngologist.
To treat outpatients for pneumonia, the Infectious Diseases Society of America recommends, in no particular order, a macrolide, doxycycline, amoxicillin (with or without clavulanic acid), or a quinolone. There is no certainty of cure in infectious diseases practice, and, in the opinion of the present writer, the cautious physician would do well to try to make the correct diagnosis by microbiologic means. When this cannot be done, he/she should advise his/her patients of this fact and keep in close touch with them for the first few days rather than feel content in having “covered” them with “empiric” antibiotic therapy. Treatment is initially begun in most cases without a diagnosis being known. Macrolides, tetracyclines, and quinolones are effective against mycoplasmas and Chlamydophila that are more likely to cause outpatient than inpatient pneumonia. The relatively high rate of resistance of pneumococci to macrolides or doxycycline seems to favor the use of a quinolone. In Sweden, the recommended drug for outpatient treatment of pneumonia is penicillin.
The importance of the decision to hospitalize or even to directly admit to intensive care cannot be overemphasized, and Pneumonia Patient Outcomes Research Team (PORT) scoring should be used to help decide whether hospitalization is needed. Pneumococcal pneumonia caused by organisms that are susceptible or intermediately resistant to penicillin responds to treatment with penicillin, one million units intravenously every 4 hours, ampicillin, 1g every 6 hours, or ceftriaxone, 1g every 24 hours. Ease of administration favors the use of ceftriaxone. The principal problem is that at the time treatment is begun, the etiology is likely not to be known. If a Gram stain of sputum at admission shows pneumococci, ceftriaxone is the preferred drug, unless the patient is extremely ill, in which case vancomycin should be added until the susceptibility of the infecting organism is known.
Patients who are treated for pneumococcal pneumonia with an effective antibiotic generally have substantially reduced fever and feel much better within 48 hours. Based on all the foregoing considerations, if a patient has responded to treatment with a beta-lactam antibiotic, this therapy should be continued even if the antibiotic-susceptibility test labels the causative organism as resistant. If, however, a clear response is not observed and the organism is resistant, therapy should be changed in accordance with susceptibility testing results.
The optimal duration of therapy for pneumococcal pneumonia is uncertain. Pneumococci are not readily detected in sputum microscopically by culture more than 24 hours after the administration of an effective antibiotic. Experience obtained early in the antibiotic era showed that 5 to 7 days of therapy sufficed, and a small-scale study in the 1950s showed that a single dose of procaine penicillin, which maintains an effective antimicrobial level for as long as 24 hours, could cure otherwise healthy young adults of pneumococcal pneumonia. Nevertheless, the tendency of the medical profession has been to prolong therapy and, in the absence of data to prove additional benefit, most physicians now treat pneumonia for 10 to 14 days. Three to 5 days of close observation with parenteral therapy for pneumococcal pneumonia and a final few days of oral treatment, in all not exceeding 5 days after the patient has become afebrile (temperature <99oF), may be the best approach.The overall duration of therapy should not exceed 10 days. Failure of the patient to defervesce within 3 to 5 days should stimulate a review of the organism’s antibiotic susceptibility, as well as a search for a loculated infection such as empyema.
Pneumococcal meningitis has been treated with 12 to 24 million units of penicillin every 24 hours, 2g ceftriaxone every 12 hours or 2mg cefotaxime every 6 hours. Any of these regimens are effective against antibiotic-susceptible S. pneumoniae and may be effective against intermediately resistant ones; pharmacokinetic considerations and achievable cerebrospinal fluid (CSF) levels favor the use of ceftriaxone. During treatment of resistant strains, beta-lactam antibiotics are likely not to achieve therapeutic levels in CSF. This explains why, until susceptibility results are reported, vancomycin is recommended along with a beta-lactam. In patients who have major penicillin and cephalosporin allergies, vancomycin and/or imipenem can be used; 1 to 2% of patients who have had life-threatening reactions to cephalosporins have an adverse reaction to a carbapenem. Unless the history suggests a life-threatening reaction to a beta-lactam, ceftriaxone or cefotaxime are preferred.
In treating pneumococcal meningitis, addition of dexamethasone, 10mg four times daily, leads to a distinctly better outcome. Because of the possibility that steroids may diminish the penetration of antibiotics into the central nervous system (CNS), patients receiving these agents should be observed particularly closely; repeat spinal taps may be needed to document abatement of CSF abnormalities, particularly if there is any suggestion of a delayed clinical response. In any case, steroid administration should not be continued beyond the recommended 4 days.
Pneumococcal endocarditis is associated with rapid destruction of heart valves, and all patients with this disease should be evaluated from the start by a cardiologist and/or a cardiovascular surgeon. Initial therapy should include vancomycin and ceftriaxone until the results of minimal bactericidal concentration testing are known. An aminoglycoside may inhibit the bactericidal activity of beta-lactam antibiotics and should not be added unless synergy in vitro is documented to occur.
Nonantibiotic adjunctive therapy
Corticosteroids, statins, and macrolides all exhibit a variety of anti-inflammatory effects. The use of steroids in treating meningitis has been discussed earlier in this chapter. Randomized prospective studies have, in fact, shown no benefit from the addition of corticosteroids in treating pneumonia, but a large prospective study is currently underway within the US Veterans Affairs health care system. Patients who are already on treatment with a statin at the time of admission for pneumococcal pneumonia have better outcomes than those who are not; a prospective study in which patients are randomized to receive a statin has not been reported. Several case control studies have compared outcomes in patients receiving a macrolide and a beta-lactam with those in patients receiving a macrolide alone. Results have favored the former group but, once again, a prospective study has not been done.
Are there issues of anti-infective resistance?
The subject of pneumococcal resistance to antibiotics is complicated because definitions have changed and susceptibility patterns have evolved, but these definitions will dictate good clinical practice, and clinicians need to understand them. In 2008, after two decades of increasing emphasis on the prevalence of penicillin-resistant pneumococci, the definitions of susceptibility were changed to reflect the site of infection and the route of therapy.
For infections other than those involving the CNS that are treated with parenteral penicillin, susceptibility, intermediate resistance and resistance to penicillin are now defined as mean inhibitory concentration (MIC) less than 2μg/mL, 4μg/mL, and greater than or equal to 8μg/mL, respectively.
If oral penicillin is to be used for therapy, the old definitions apply, such that organisms with MIC less than 0.06μg/mL are called susceptible, those with a MIC of 0.1 to 1.0μg/mL have intermediate resistance and isolates with MIC greater than or equal to 2μg/mL are called resistant, reflecting the substantially lower tissue levels achievable with that therapy. In CNS infection, organisms with MIC less than or equal to 0.06μg/mL are susceptible; those with MIC greater than or equal to 0.12μg/mL are regarded as resistant.
Similar approaches have been developed to define susceptibility to amoxicillin, ceftriaxone, and other beta-lactam antibiotics. For example, MICs for susceptibility, intermediate resistance, and resistance to amoxicillin are defined simply as less than or equal to 2μg/mL, 4μg/mL, and greater than or equal to 8μg/mL, respectively, reflecting the concept that no physician would use oral therapy to treat a CNS infection. For ceftriaxone, there are separate definitions for CNS and non-CNS infections.
By these definitions, at the present time in the United States:
65% of isolates appear to be susceptible to levels achieved with oral penicillin; 17% are intermediately resistant, and 17% are resistant.
93% of all pneumococci are susceptible to penicillin if given parenterally or amoxicillin if given orally; 5% are intermediate, and 2% are resistant.
In cases of meningitis, 65% of organisms are susceptible to penicillin and 35% are resistant (no intermediate resistance is defined).
For ceftriaxone, in non-CNS infections, 94% of organisms are susceptible, 5% are intermediate and 1% are resistant; in CNS infections, these percentages are 88%, 7%, and 5%, respectively.
Pneumococci with low MICs for penicillin remain susceptible to most other antibiotics, whereas strains that have reduced susceptibility to penicillin tend to be multiply resistant. At present, in the United States:
approximately 20% of all pneumococci are resistant to macrolides.
8% are resistant to clindamycin.
30% are resistant to trimethoprim/sulfamethoxazole.
18% are resistant to doxycycline.
2% are resistant to the newer quinolones. In general, greater than 98% of isolates remain susceptible to fluoroquinolones, probably because these drugs are not used to treat children.
nearly all pneumococci remain susceptible to ceftaroline, vancomycin, linezolid, or tigecycline
How do patients contract this infection, and how do I prevent spread to other patients?
S. pneumoniae is largely confined to humans, generally to the respiratory tract, and is spread from person to person by intimate contact or by aerosol.
A single nasopharyngeal swab yields pneumococci in 5 to 10% of healthy adults and 20 to 40% of healthy children.
The percentage increases to 40 to 60% or greaterin toddlers and young children in daycare, and is even greater among all children in more primitive societies.
The numbers of organisms present in the nasopharynx of infants and young children is much greater than in adults, a fact that explains the high false-positive rate for the pneumococcal urine antigen test (and its lack of utility) in those populations (see later in this chapter, laboratory diagnosis).
In adults, close, crowded living conditions such as occur in military camps,prisons, shelters for the homeless, and nursing homes are associated with epidemics, but contact in schools or in the workplace is generally not.
The common feature for outbreaks is that, in addition to crowding and close contact, the population has some additional feature(s) that contribute(s) to susceptibility to infection, often a concurrent outbreak of a viral respiratory infection and/or physical or emotional stress.
Pneumococcal colonization stimulates production of anticapsular antibody.
In infants and young children, otitis media follows acquisition of a new colonizing strain. After a few weeks, protection reflects the presence of antibody.
Adults also develop antibody after colonization.
An important clinical corollary of this observation is that persons who are not able to mount antibody responses remain susceptible to pneumococcal disease as long as they remain colonized (see later in this chapter, predisposing factors).
Before the widespread use of conjugate pneumococcal vaccine (see later in this chapter, prevention) in infants and toddlers, the incidence of invasive pneumococcal disease was:
100 cases per 100,000 population of infants
12 cases per 100,000 population of young adults
100 cases per 100,000 population of persons aged greater than or equal to 70 years
In the past few years, thanks to that vaccine, the incidence in these groups is 25, 8, and 60, respectively.
In certain populations, including African-Americans, Native Americans (particularly Alaskans) and certain aboriginal populations, the incidence may be up to 10-fold greater, although it is unclear to what extent genetic or environmental factors are responsible.
Infection control issues:
Since several steps intervene between exposure to an organism, colonization, and development of infection, direct contagion is not generally an issue. Spread of pneumococcal infection within a hospital environment is exceedingly rare. There are no recommendations beyond universal precautions.
Two kinds of pneumococcal vaccine are currently available.
Pneumococcal capsular polysaccharide vaccine, marketed as Pneumovax®, contains 25μg of capsular polysaccharides from each of 23 common infecting serotypes of S. pneumoniae (PPV23).
Protein-conjugate pneumococcal vaccine contains capsular material from 13 pneumococcal serotypes, Prevnar13® (PCV13). The capsular polysaccharides are each bound chemically to a nontoxigenic protein that closely resembles diphtheria toxin.
PPV23. Many studies and meta-analyses, based largely on case control studies, have shown approximately 60 to 70% protection against invasive pneumococcal disease and slightly lower protection against nonbacteremic pneumococcal pneumonia. The problem with pneumococcal vaccination is that those who are in greatest need of it are least likely to generate good antibody responses.
Older persons and those who have chronic lung or heart disease have lower antibody levels after vaccination, and their immunoglobulin (Ig) G is less active in functional assays in vitro.
Persons who have immunosuppressive conditions that place them at highest risk of pneumococcal infection, such as multiple myeloma, Hodgkin disease, splenectomy, lymphoma, nephrotic syndrome, renal failure, cirrhosis, sickle cell disease, bone marrow transplantation, and human immunodeficiency virus (HIV) infection respond poorly, if at all, to polysaccharide antigens.
Persons who have recovered from pneumococcal pneumonia respond initially to vaccination, but no longer have detectable levantibody at 6 months.
The Immunization Practices Advisory Committee of the Centers for Disease Control and Prevention (CDC) now recommends PPV23 for:
All persons over the age of 2 years who are at substantially increased risk of developing pneumococcal infection and/or a serious complication of such an infection. General categories included within these recommendations are those persons who:
(1) are over the age of 65 years;
(2) have anatomic or functional asplenia, CSF leak, diabetes mellitus, alcoholism, cirrhosis, chronic renal insufficiency, chronic pulmonary disease (including asthma), or advanced cardiovascular disease;
(3) have an immune compromised condition that is associated with increased risk of pneumococcal disease, such as multiple myeloma, lymphoma, Hodgkin disease, HIV infection, organ transplantation, or chronic use of glucocorticosteroids;
(4) are genetically at increased risk, such as Alaskan and American Natives(5) who live in special environments where outbreaks may occur, such as nursing homes
Recommendations regarding revaccination seem to be somewhat inconsistent because the committee advocates a single revaccination in persons over the age of 65 years as well as most others. Since antibody levels decline and there is no anamnestic response, it seems more reasonable simply to recommend:
Revaccination at 5 to 7 year intervals, particularly in adults over the age of 65 years, who will have a minimal local reaction. Hyporesponsiveness (the failure to make antibody to a second vaccination when given soon after a first vaccination) is not seen 5 years after prior vaccination.
Revaccination every 5 years for persons who are at highest risk of recurring pneumococcal infection—those who have undergone splenectomy or have a CSF leak.
PCV. Infants and young children do not make antibody after vaccination with pure polysaccharide antigens. However, when pneumococcal capsular polysaccharides have been covalently conjugated to carrier proteins, the resulting antigens are recognized as T-cell dependent; they stimulate good antibody responses in children under the age of 2 years and induce immunologic memory.
In a field trial involving 38,000 infants and toddlers, vaccination with PCV7 produced a brilliant response, being followed by a 90% decrease in pneumococcal meningitis. Widespread introduction of PCV7 in the pediatric population in 2000 decreased disease due to vaccine serotypes by ≥90%, both in vaccinated and nonvaccinated subjects. The decrease in incidence in unvaccinated persons is called the “herd effect;” it occurs because PCV immunizes against colonization as well as against infection, and that effect reduces the prevalence of vaccine-type pneumococci in the population at large.
An untoward result of widespread vaccination has been the appearance of new strains that are not contained in the vaccine; these are called replacement strains. The principal one, type 19A, has become the predominant cause of pneumococcal disease in all age groups in the United States. This serotype is included in PCV13 which was put into widespread use in 2010.
PCV13 versus PPV23 in adults. Hopes that protein conjugation would greatly enhance antibody responses have not been fulfilled. A comparison of antibody levels and opsonic effect after vaccination with PPV23 versus PCV showed remarkably few differences or modestly higher antibody levels after PCV.
On the other hand, some congenital nonresponders to PPV23 do respond to PCV, and two large studies in African patients with acquired immune deficiency syndrome (AIDS) showed no protection from PPV23 vs. excellent protection in the year following PCV7, respectively. A large field trial of PCV13 has shown that PPV23 protects adults against pneumococcal pneumonia and IPD.
In June, 2012, the Advisory Council on Immunization Practices of the CDC recommended that:
(1) adults aged 19 years or older with immunocompromising conditions, functional or anatomic asplenia, CSF leaks, or cochlear implants, and who have not previously received PCV13 or PPSV23 receive a single dose of PCV13 followed by a dose of PPSV23 at least 8 weeks later
(2) adults aged 19 years or older with immunocompromising conditions, functional or anatomic asplenia, CSF leaks or cochlear implants, and who have previously received one or more doses of PPSV23 receive a dose of PCV13 one or more years after the last PPSV 23 dose was received. For those that require additional doses of PPSV23, the first such dose should be given no sooner than 8 weeks after PCV13 and at least 5 years since the most recent dose of PPSV23.
The lack of convincing differences in responses to the two vaccine preparations and the fact that widespread use of PCV13 in children is expected to be followed by disappearance from the population of vaccine strains suggests to some authorities that routine vaccination of adults with PCV13 in the United States will be of little benefit.
Protein vaccines. Vaccines utilizing conserved protein antigens might bypass the problems relating to polysaccharide vaccines. Pneumolysin is a major virulence factor of S. pneumoniae and can, when inoculated intratracheally into experimental animals, cause pulmonary infiltration. Antibody is protective in such animals. A pneumolysoid vaccine is currently in development. Antibody to certain surface expressed proteins such as PspA (pneumococcal surface protein A) or the Pht (pneumococcal histidine triad) proteins has been shown to be protective in experimental animals, and these are also under study as vaccine candidates.
What host factors protect against this infection?
S. pneumoniae was the first organism to be shown to behave as what is now regarded as an extracellular bacterial pathogen. The principal defense against infection is ingestion by dendritic and phagocytic cells; in the absence of antibody, it resists phagocytosis and replicates extracellularly in mammalian tissues.
The polysaccharide capsule is chiefly responsible for resistance to ingestion and killing by host phagocytic cells. Except for strains that cause conjunctivitis, nearly all pneumococci that cause disease in humans are encapsulated.
A total of 91 different pneumococcal capsular polysaccharides have been recognized; these form the basis for the common identification system.
It is important to the clinician to be familiar with the concept of capsular types because of their importance in new formulations of pneumococcal vaccine (see later in this chapter).
Antibody to capsule is the principal defense mechanism against infection due to pneumococcus, but antibody to pneumolysin (the only recognized important toxin of S. pneumoniae) and to surface expressed proteins will become increasingly important, as will be mentioned during the consideration of pneumococcal vaccine.
Once nasopharyngeal colonization has taken place, infection may result if the organisms are carried into cavities from which they are not readily cleared.
Under normal circumstances, when bacteria find their way into the Eustachian tubes, sinuses, or bronchi, clearance mechanisms, chiefly ciliary action, lead to their rapid removal.
If conditions such as coexisting viral infection, exposure to pollutants, or an allergic condition cause edema that obstructs the opening of the Eustachian tube into the pharynx or the ostium of a paranasal sinus, clinically recognizable infection may result.
Similarly, glottal and cough reflexes and ciliary activity of bronchial epithelial cells prevent pneumococci from infecting the lower airways.
Damage to ciliated bronchial cells or increased production of mucus, whether chronic (for example, from cigarette smoking or occupational exposure) or acute (from influenza or some other viral infection), may prevent the clearance of inhaled or aspirated organisms, predisposing the patient to infection.
Respiratory viral infection, especially that due to influenza virus, plays a prominent role in predisposing the patient to pneumococcal pneumonia. Upregulation of surface receptors during viral infection may enhance pneumococcal adherence and invasion. Bacteria are certainly less well cleared from the airways because of viral-induced damage.
Pneumococcal disease is greatly increased in people with altered pulmonary clearance, such as those who have chronic bronchitis, asthma, or chronic obstructive pulmonary disease. Only in the past few years has evidence clearly associated cigarette smoking with susceptibility to pneumonia. It is an interesting sign of the times that Heffron’s classical treatise on pneumococcus published in 1939 had a section on inhalation of “noxious substances” yet did not mention cigarette smoking.
Host risk factors
Defective antibody formation, whether congenital or acquired, has the greatest impact on susceptibility to pneumococcal infection.
Bruton’s original description of congenital agammaglobulinemia stressed the prominence of S. pneumoniae as an infecting agent. Pneumococcus is also a major cause of serious infection in acquired agammaglobulinemia (common variable immunodeficiency) and perhaps in IgG subclass deficiency as well.
Diseases characterized by an inability to make IgG, such as multiple myeloma, lymphoma, and HIV infection, all predispose to pneumococcal infection. The increase in susceptibility in such persons may be of a staggering magnitude.
Multiple myeloma is often first recognized when an affected person develops pneumococcal pneumonia.
The incidence of invasive pneumococcal disease in patients with AIDS is increased nearly 100-fold over an age-matched non-HIV infected population.
Defective function of polymorphonuclear leukocytes (PMNs) is also highly associated with pneumococcal infection. Examples include renal insufficiency and diabetes mellitus. The predisposition from alcoholism and chronic liver disease is in part due to the adverse effect on PMNs but is also multifactorial.
The susceptibility of aged persons to pneumococcal pneumonia is multifactorial, reflecting senescence of the immune system because of diminished production of Igs (or production of poorly functional ones), impaired response to cytokines, and general debilitation caused by weakening of the gag reflex, malnutrition, and the presence of other diseases.
The incidence of alcohol abuse in pneumococcal disease has been shown to be high since the first part of the twentieth century. The effect of alcoholism is multifactorial, involving lifestyle (such as cold exposure and malnutrition), suppression of the gag reflex, and possibly deleterious effects on PMN function. Anemia may also predispose to pneumococcal pneumonia by uncertain mechanisms.
A wintertime increase in pneumococcal pneumonia adults has long been noted, perhaps associated with viral infections.
Pneumococcal pneumonia is greatly increased in the 6 months following hospitalization for any cause.
Other factors such as cold exposure, stress, and fatigue may predispose to pneumococcal pneumonia by unknown mechanisms. The death rate in the first year or two after pneumococcal pneumonia is also very high.
Splenectomy is often mentioned as a factor that predisposes to pneumococcal infection; this concept is only partly true. In the absence of anticapsular antibody, the spleen is the principal organ that clears pneumococci from the blood stream. Persons who have had splenectomy or who have dysfunctional spleens (for example those with sickle cell disease) are not necessarily likely to have more frequent pneumococcal infections, but when they are infected, they are susceptible to rapidly progressive, overwhelming pneumococcal disease. The heralding event in an outbreak of pneumococcal pneumonia in a metropolitan prison was the rapid, septic death of two prisoners, both of whom had previously undergone splenectomy. Pneumococcal disease progressed so rapidly in these cases that pneumonia was not initially detectable clinically or even with certainty by chest radiographs, although it was seen at autopsy.
What are the clinical manifestations of infection with this organism?
S. pneumoniae causes infection of the middle ear, sinuses, trachea, bronchi, and lungs by direct spread of organisms from the nasopharyngeal site of colonization and causes infection of the CNS, heart valves, bones, and joints by hematogenous spread; the peritoneal cavity may be infected by local extension along the female genital tract or hematogenously. Infection of the pleura or peritoneal cavity and also of the CNS may occur by direct extension or by hematogenous spread; in any individual case, the route of infection can usually not be determined.
Of 136 cases of invasive pneumococcal infection at the Houston Veterans Affairs Medical Center seen during a 9-year period, 116 patients (85%) had pneumonia, of whom three also had empyema. Seven had bacteremia with no apparent source, five had meningitis, five had spontaneous bacterial peritonitis, three had septic arthritis, two had endocarditis, and individual patients had osteomyelitis and/or localized abscesses. Multiple areas of involvement were seen in nine patients.
Bacteremia. Bacteremia that occurs without an apparent source or focus of infection is called primary bacteremia. In a recent population-based study of bacteremic pneumococcal disease in adults in Israel, pneumonia was present in 71% of cases, meningitis was present in 8%, and otitis media or sinusitis in 4%; bacteremia was regarded as primary in 18%. Primary bacteremia has always been more common in children than adults; when therapy has not initially been given, a focus of infection has often become apparent.
Otitis media. In cases of otitis media, S. pneumoniae has historically been the most common isolate, being identified in about 40 to 50% of cases in which an etiologic agent is isolated or in 30 to 40% of all cases. Nontypeable H. influenzae, historically the next most common organism, is more likely to predominate in highly vaccinated populations. Pneumococcus is the most prevalent pathogen in otitis media in adults as well. As noted above, prior infection by a respiratory virus, allergy, or air pollutants contribute to pathogenesis by causing inflammation and blocking the opening to the Eustachian tube, thereby trapping bacteria in the middle ear. The diagnosis is made by the presence of pain and fever, with redness and bulging of the tympanic membrane that fails to respond to positive air pressure. Pneumococcal mastoiditis has been only a rare complication of otitis media in the antibiotic era.
Sinusitis. Acute purulent sinusitis is caused by the same organisms as acute otitis media; thus, S. pneumoniae predominates or is second to H. influenzae. The pathogenesis of infection is also similar, with a prominent predisposing role for congestion of the mucosal membranes. Accumulation of fluid in the paranasal sinus cavities, even during simple colds, provides a medium for bacterial proliferation and subsequent infection. This condition has been shown to be greatly overdiagnosed. Often the condition is biphasic, with an initial upper respiratory infection that appears to be viral, followed by a worsening, with the appearance of purulent secretions, malaise, fever, tenderness over one or more sinuses and or pain in a tooth. Diagnosis depends upon these clinical features; computed tomography scans of sinuses regularly show fluid in patients who have harmless, presumably viral upper respiratory infections without symptoms of sinusitis, so this finding does not indicate the presence of bacterial sinusitis.
Acute bronchitis. In persons who do not have chronic underlying bronchopulmonary disease, acute bronchitis is thought to be nearly always due to viral infection. Acute exacerbations of bronchitis in patients with chronic bronchitis, asthma, or obstructive lung disease may be caused by S. pneumoniae although H. influenzae is far more commonly implicated. A clinically recognizable exacerbation of the chronic disease is highly associated with acquisition of a new pneumococcal strain.
Pneumonia. Pneumonia results when nonimmunologic and immunologic mechanisms fail to prevent access of pneumococci to the alveoli and their subsequent replication. Most patients who develop pneumococcal pneumonia have one or more of the predisposing conditions that are summarized above, such as a preceding viral respiratory infection, cigarette smoking, chronic obstructive pulmonary disease, alcohol abuse, neurological disease (cerebrovascular accidents, seizures, and dementia), malignancy, liver disease (hepatitis and/or cirrhosis), congestive heart failure, diabetes mellitus, or HIV infection.
Cough, fatigue, fever, chills, sweats, and shortness of breath are the most frequent symptoms of pneumonia; these are all more prominent in younger than in older patients.
Patients usually appear ill and have a grayish, anxious appearance that differs from that of persons with viral or mycoplasmal pneumonia.
Temperature may be elevated to 102oF, the pulse to greater than or equal to 110 beats per minute, and the respiratory rate to greater than 20 per minute.
Elderly patients may have only a slight temperature elevation or be afebrile but are more likely to have an elevated respiratory rate.
The sudden onset of shaking chills followed by the appearance of cough and rusty sputum has been called a “classical presentation” of pneumococcal pneumonia, but is uncommon.
Occasionally reveals diminished respiratory excursion on the affected side.
Increased fremitus is often overlooked but is very useful in diagnosing pneumonia.
Dullness to percussion is present in approximately 50% of cases.
Crackles on careful auscultation are heard in nearly all cases but, in patients with chronic lung disease, it is often difficult to be certain that such sounds signify the presence of pneumonia.
Bronchial or tubular breath sounds may be heard if consolidation is present.
Flatness to percussion at the lung base and an inability to detect the expected degree of diaphragmatic motion with deep inspiration suggest the presence of pleural fluid.
Unless all the vital signs are normal, which substantially reduces the likelihood of pneumonia, no set of physical findings can reliably replace the chest X-ray in diagnosing the presence or absence of pneumonia.
The finding of a heart murmur raises concern about endocarditis, a rare but serious complication.
Confusion, obtundation, or particularly neck stiffness suggest the presence of meningitis.
Radiographic findings. In most cases of pneumococcal pneumonia, chest radiography reveals:
An area of infiltration involving one or more segments within a single lobe. Multiple lobes may, however, be involved. Airspace consolidation is detected radiographically in most cases, and is more frequent in bacteremic cases
An air bronchogram, which reflects especially dense air-space consolidation, highly correlates with bacteremia.
Computed tomography may reveal cavitation in 6 to 7% of cases, but this finding does not alter the prognosis. A thick-walled lung abscess is distinctly rare, and its finding raises the likelihood of other etiologic agents.
Although careful prospective study may reveal pleural effusion in up to 40% of patients with pneumococcal pneumonia, only 10% have sufficient amounts of fluid to aspirate, and in only a minority of these, perhaps 2% of the total, is empyema present.
General laboratory findings
25% of patients with pneumococcal pneumonia have a hemoglobin level of less than or equal to 11g/dL.
The majority of patients have leukocytosis (a white blood cell count [WBC] of >12,000/mm3),
But 25% may have normal WBC counts, at least at the time of admission.
A WBC count less than 6,000/mm3 occurs in 5 to 10% of persons hospitalized for pneumococcal pneumonia and indicates a very poor prognosis.
A low serum albumin level may reflect malnutrition—and therefore indicates a predisposing condition, or may appear as a manifestation of sepsis.
Serum bilirubin may be increased to 3 to 4mg/dL; the pathogenesis of this abnormality is multifactorial, with hypoxia, hepatic inflammation, and breakdown of red blood cells in the lung all thought to contribute.
Complications.Empyema, the most common infectious complication of pneumococcal pneumonia, occurs in approximately 2% of cases. Persistence of fever, even if only low grade, and leukocytosis after 4 to 5 days of appropriate antibiotic treatment of pneumococcal pneumonia is suggestive of empyema, and this diagnosis is even more likely if the radiograph shows persistence of any pleural fluid. Under such conditions, attempts should be undertaken to drain the fluid completely. (As a general matter, drainage is indicated if pleural fluid is present at the time of diagnosis of pneumococcal pneumonia.) The presence of frank pus in the pleural space, a positive Gram stain or fluid with a pH of less than or equal to 7.1 is an indication for aggressive and complete drainage with repeated needle aspiration or prompt insertion of a chest tube. If no response is seen, immediate removal of infected material by pleuroscopy or open thoracotomy is then indicated.
Acute cardiac events have recently been recognized as important noninfectious complications of pneumococcal pneumonia. In a recently reported series, of 170 veterans hospitalized for this disease:
33 (19.4%) had at least one major cardiac complication including:
12 (7%) with acute myocardial infarction (of whom two also had arrhythmia and five had new-onset or worsening congestive heart failure [CHF]).
Eight (5%) with new-onset atrial fibrillation or ventricular tachycardia that was transient in every case.
13 (8%) with newly diagnosed or worsening CHF, without myocardial infarction or new arrhythmias.
Mechanisms for these cardiac events include: (1) increased local inflammatory response in vulnerable plaques in coronary arteries; (2) decreased oxygen supply because of ventilation/perfusion mismatch; and (3) increased cardiac demand related to fever and shunting.
Meningitis. S. pneumoniae is the most common cause of sporadic bacterial meningitis. No distinctive clinical or laboratory features of pneumococcal meningitis enable the physician to suspect S. pneumoniae over other causatie bacteria.
Headache, fever, and stiff neck or neck pain predominate. A clouded sensorium reflects the involvement of the superficial cortex by the inflammatory process.
A spinal tap should be done urgently, without even delaying for a computed tomography scan of the head if no localizing signs are present on neurological examination.
CSF generally contains a WBC count of greater than 300 with a neutrophil predominance, a glucose level of less than 30mg/dL and a protein level greater than 100mg/dL.
Using current laboratory techniques, examination of a Gram-stained specimen of CSF provides the correct diagnosis in nearly all cases unless 3 to 6 hours have passed since the administration of an effective antibiotic.
Immunologic detection of pneumococcal capsular material (“bacterial antigen”) generally does not add information beyond what is determined by Gram stain, although nuclear probes may eventually be useful in this situation.
Other infections. As noted above, S. pneumoniae can be implicated in a wide variety of infectious states.
For unclear reasons, isolated or epidemic conjunctivitis is caused by unencapsulated pneumococci.
Pneumococcal endocarditis is seen once or twice per decade at a large tertiary care hospital; most infections involve previously normal heart valves, and the disease tends to be rapidly progressive and severe.
Pneumococcal pericarditis has become exceedingly rare in the antibiotic era.
Pneumococci reach the peritoneum via the blood stream, causing peritonitis; this generally occurs in the absence of a documented source of infection elsewhere.
Peritonitis occurs via hematogenous spread in patients who have pre-existing ascites.
In patients who do not have pre-existing ascites, pneumococci may be carried to the peritoneal cavity via the female reproductive tract, with or without clinically recognizable infection of the female reproductive organs (e.g., salpingitis), or may follow bowel perforation.
Septic arthritis occurs spontaneously in natural or prosthetic joints and ocurs with increased frequency in patients with rheumatoid arthritis.
Osteomyelitis in adults tends to involve the vertebral bones. Epidural and brain abscesses are rarely described.
Soft tissue infections occur, especially in persons who have connective tissue diseases or HIV infection.
What common complications are associated with infection with this pathogen?
Empyema, a complication of pneumonia, is described above. Infection of other organs may be a complication of bacteremia that appears during pneumonia or other respiratory infection or may result from bacteremia without a recognized focus, as discussed earlier in this chapter.
How should I identify the organism?
Diagnostic microbiology. An etiologic role for pneumococcus in pneumonia is strongly suggested by microscopic demonstration of large numbers of PMNs, few epithelial cells, and numerous, slightly elongated gram-positive cocci in pairs and chains in a Gram-stained sputum.
Attempts to make a diagnosis based on an inadequate sputum specimen are largely responsible for claims that microscopic examination and culture of sputum are not reliable.
A reliable sputum sample should reveal areas with WBC counts of 10 to 20 and no epithelial cells visible under 1,000x magnification. More than 25 pneumococci are generally present per microscopic field, although occasionally, far fewer may be seen.
If sufficient numbers of inflammatory cells are not present, relevant material has not been obtained.
If many epithelial cells are detected, the finding of bacteria cannot be trusted to reflect what is present in the bronchi or lungs.
A good-quality sputum specimen is far more likely to be obtained by a physician, who best understands its central role in establishing an etiologic diagnosis and determining therapy, than by ancillary personnel, who may not.
If patients are able to provide an adequate specimen and have not received antibiotics for more than 12 hours, Gram stain and culture each are more than 85% likely to reveal pneumococci in the expectorated sputum of patients with pneumococcal pneumonia.
Other tests, such as antigen detection or polymerase chain reaction, that look for pneumococci in the sputum are not helpful because they are confounded by the potential problem of detecting carriage rather than infection.
The Binax® test detects pneumococcal cell wall polysaccharide in the urine of approximately 75% of patients who have bacteremic pneumococcal pneumonia and a lower percentage of those with pneumonia without bacteremia.
In adults, this test is regarded as specific for diagnosing pneumococcal pneumonia.
In contrast, in children, this test is positive with pharyngeal colonization, and it is not useful diagnostically.
Culture. Pneumococcus appears on a blood agar plate as an alpha-hemolytic streptococcus.
This microbiological observation is important clinically; because alpha-hemolytic streptococci predominate in saliva, it can be difficult to identify pneumococci in sputum cultures unless a good-quality specimen has been obtained.
Colonies can be identified within 12 to 14 hours, and identification can be made soon thereafter.
Blood cultures are generally positive within 12 hours of being placed in the incubator.
How does this organism cause disease?
Pneumococci colonize the nasopharynx by adhering to respiratory epithelial cells and proliferating. From their location as colonizers of the nasopharynx, pneumococci may be carried locally to adjacent areas such as the middle ear, the sinuses, the bronchi, and the lungs. If they are not cleared by normal defense mechanisms, their capacity to cause an intense inflammatory reaction leads to disease.
Remote infection may result from bacteremia during infection of the respiratory tract. Infrequently, colonizing pneumococci may invade mucous membranes directly, making their way directly to lymphatics or to the blood stream and causing infection in the CNS or at other sites in the body.
Pathogen recognition receptors on the surface of mammalian phagocytic cells play a major role in innate immunity.
Peptidoglycan and lipoteichoic acid interact with cluster of differentiation (CD)14, stimulating toll-like receptor (TLR) 2.
Pneumolysin interacts with TLR4 to induce nuclear factor kappa B (NF-κB).
The result is a “two-edged sword.”
These stimuli facilitate uptake of pneumococci in the absence of antibody to any of its constituents.
At the same time, they stimulate a vigorous inflammatory response by upregulating production of inflammatory cytokines interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF) alpha, thereby contributing to pneumococcal disease, which is largely a result of inflammation and is often severe in direct proportion to the intensity of the inflammatory response.
All pneumococci produce pneumolysin, a thiol-activated toxin that inserts into the lipid bilayer of cell membranes via its interaction with cholesterol.
Pneumolysin is cytotoxic for phagocytic and respiratory epithelial cells and causes inflammation by activating complement and inducing the production of TNF-alpha and interleukin-1.
Injection of pneumolysin into rat lung causes all the histologic findings of pneumonia, and immunization of mice with this substance before pneumococcal infection or challenge with genetically engineered pneumococci that do not produce it is associated with a significant reduction in virulence.
Proteins on the pneumococcal surface that bind to choline residues may mediate attachment to and penetration of mammalian cells, particularly if these cells have been upregulated by prior cytokine exposure.
Pneumococcal surface protein A is present on the surface of nearly all pneumococci and exerts an antiphagocytic force, perhaps by blocking deposition of complement.
Despite some antigenic variability, antibody raised against pneumococcal surface protein A protects experimental animals to a greater or lesser extent against challenge with the same or different strain, and genetically engineered mutants that lack it have reduced virulence for mice.
Human antibody to this protein protects mice against pneumococcal infection and may protect humans against pneumococcal colonization.
This substance is a major constituent of a vaccine that is currently in development (see vaccination).
In addition to pneumococcal surface adhesin A, a surface-expressed permease, neuraminidase and autolysin are also thought to contribute to pathogenesis.
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- OVERVIEW: What every clinician needs to know
- Pathogen name and classification
- What is the best treatment?
- How do patients contract this infection, and how do I prevent spread to other patients?
- What host factors protect against this infection?
- What are the clinical manifestations of infection with this organism?
- What common complications are associated with infection with this pathogen?
- How should I identify the organism?
- How does this organism cause disease?